It has been recognized for over a century that the anterior chamber (AC) of the eye is endowed with remarkable immunologic properties that permit the long term survival of histoincompatible allografts that are briskly rejected at other body sites. This immune privilege is an adaptive mechanism for restraining immune-mediated inflammatory responses that can damage ocular cells that have little or no regenerative capacities. Ocular immune privilege is the product of multiple, often overlapping mechanisms that conspire to prevent the induction and expression of immune-mediated inflammation. One of these mechanisms is a dynamic, antigen-specific suppression of systemic delayed-type hypersensitivity (DTH) that occurs when antigens, alloantigenic cells, or viruses are introduced into the anterior chamber of the eye. This unique immunoregulatory mechanism has been termed anterior chamber-associated immune deviation (ACAID) and has been demonstrated with a wide range of antigens. The induction of ACAID requires the active participation of the spleen. This project will determine the respective roles of four spleen cell populations that are known to have an obligatory role in the induction and expression of ACAID: 1) B cells; 2) NK1.1 + T cells; 3) gamma/delta T cells; and 4) CD4+ T cells. The role of the splenic B cell as a tolerance inducing antigen presenting cell (APC) will be explored, both in vitro and in vivo. Studies will determine if NK1.1+ T cells and gamma/delta T cells act as ancillary cytokine producing cells that create an immunosuppressive milieu that promotes the development of CD4+ afferent suppressorT cells that induce the development of CD8+ regulatory T cells that are the endstage effector cells of ACAID and act to suppress the expression of DTH. The long-range goal of this project is to gain a better understanding of the various immunoregulatory processes that are unique to the eye and that protect the delicate ocular tissues from unwitting immune-mediated injury that can lead to blindness. With this information, we hope to eventually devise methods to enhance immune privilege in conditions that benefit the host (e.g., corneal transplantation). In some cases, it may be desirable to abrogate immune privilege to promote the immune-rejection of sight- and life-threatening ocular neoplasms.